DNA databanks and consent: A suggested policy option involving an authorization model

Background

Genetic databases are becoming increasingly common as a means of determining the relationship between lifestyle, environmental exposures and genetic diseases. These databases rely on large numbers of research subjects contributing their genetic material to successfully explore the genetic basis of disease. However, as all possible research questions that can be posed of the data are unknown, an unresolved ethical issue is the status of informed consent for future research uses of genetic material.

Discussion

In this paper, we discuss the difficulties of an informed consent model for future ineffable uses of genetic data. We argue that variations on consent, such as presumed consent, blanket consent or constructed consent fail to meet the standards required by current informed consent doctrine and are distortions of the original concept. In this paper, we propose the concept of an authorization model whereby participants in genetic data banks are able to exercise a certain amount of control over future uses of genetic data. We argue this preserves the autonomy of individuals at the same time as allowing them to give permission and discretion to researchers for certain types of research.

Summary

The authorization model represents a step forward in the debate about informed consent in genetic databases. The move towards an authorization model would require changes in the regulatory and legislative environments. Additionally, empirical support of the utility and acceptability of authorization is required.

     

Buffy coat platelets stored in apyrase, aprotinin, and ascorbic acid in a suspended bag: combined strategies for reducing platelet activation during storage

BACKGROUND: Platelet activation is an important factor impeding the clinical effectiveness of platelet transfusions. In this study, platelet concentrates (PCs) were prepared by a novel suspended-bag buffy coat technique that was followed by the addition of a mixture of platelet activation inhibitors to the storage bag. STUDY DESIGN AND METHODS: In vitro platelet function was evaluated in PCs prepared by the suspended-bag buffy coat technique and stored at 22 degrees C for 5 days in the presence of (n = 12) or absence (n = 12) of apyrase, ascorbic acid, and aprotinin (AAA). RESULTS: Platelets from AAA- incubated PCs demonstrated mean ATP levels 17 percent (p < 0.004), 13 percent (p < 0.02), and 22 percent (p < 0.003) higher than those measured in parallel control PCs on Days 1, 3, and 5, respectively. Similarly, on Days 3 and 5 of storage, respectively, 45-percent (p < 0.001) and 50-percent (p < 0.001) greater ADP-induced maximum aggregation was observed in AAA-incubated PCs than was seen in control preparations. AAA-incubated PCs demonstrated alpha-granule membrane protein-140 expression 92 percent (p < 0.01), 133 percent (p < 0.003), and 104 percent (p < 0.001) below that in control PCs on Days 1, 3, and 5, respectively. At similar intervals, a significant increase in recovery from hypotonic shock also was observed in AAA-incubated PCs. Further, Day 5 AAA-PCs demonstrated significantly higher morphology scores and O2 consumption than did control preparations. CONCLUSION: Buffy coat platelets prepared in suspended bags and stored in the presence of AAA demonstrate significantly reduced activation and enhanced functional and metabolic activity.     

Measuring change in health status of older adults at the population level: The transition probability model

Background  

The current demographic transition will lead to increasing demands on health services. However, debate exists as to the role age plays relative to co-morbidity in terms of health services utilization. While age has been identified as a critical factor in health services utilization, health services utilization is not simply an outcome of ill health, nor is it an inevitable outcome of aging. Most data on health service utilization studies assess utilization at one point in time, and does not examine transitions in health service utilization. We sought to measure health services utilization and to investigate patterns in the transition of levels of utilization and outcomes associated with different levels of utilization.     

Safety findings from CENTURION,a phase 3 consistency study of lasmiditan for the acute treatment of migraine

BackgroundLasmiditan (LTN) is a selective 5-HT_1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION).MethodsPatients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses.ResultsOverall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks.The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks.Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents.ConclusionIn this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks.Trial registration {"type":"clinical-trial","attrs":{"text":"NCT03670810","term_id":"NCT03670810"}}NCT03670810 Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01343-2.     

Association of hemoglobin concentration and mortality in critically ill patients with severe traumatic brain injury

ABSTRACT: INTRODUCTION: The critical care management of traumatic brain injury focuses on preventing secondary ischemic injury. Cerebral oxygen delivery is dependent upon the cerebral perfusion pressure and the oxygen content of blood, which is principally determined by hemoglobin. Despite its importance to the cerebral oxygen delivery, the precise hemoglobin concentration to provide adequate oxygen delivery to injured neuronal tissue in TBI patients is controversial with limited evidence to provide transfusion thresholds. METHODS: We conducted a retrospective cohort study of severe TBI patients, investigating the association between mean 7-day hemoglobin concentration and hospital mortality. Demographic, physiologic, intensive care interventions, clinical outcomes and daily hemoglobin concentrations were recorded for all patients. Patients were all cared for at a tertiary, level 1 trauma center in a mixed medical and surgical intensive unit. Patients were divided into quartiles based on their mean 7-day hemoglobin concentration: < 90 g/L, 90 - 99 g/L, 100 - 109 g/L and > 110 g/L. Multivariable log-binomial regression was used to model the association between mean daily hemoglobin concentration and hospital mortality. RESULTS: Two hundred seventy-three patients with traumatic brain injury were identified and 169 were included in the analysis based on inclusion/exclusion criteria. Of these, 77% of the patients were male, with a mean age of 38 (SD 17) years and a median best GCS of 6 (IQR 5 - 7). One hundred fifteen patients (68%) received a red blood cell (RBC) transfusion. In RBCs administered in the ICU, the median pre-transfusion hemoglobin was 79 g/L (IQR 73 - 85). Thirty-seven patients (22%) died in hospital. Multivariable analysis revealed that mean 7-day hemoglobin concentration < 90 g/L was independently associated with an increased risk of hospital mortality (RR 3.1, 95% CI 1.5 - 6.3, p = 0.03). Other variables associated with increased mortality on multivariable regression were insertion of external ventricular drain, age and decreased GCS. Red blood cell transfusion was not associated with mortality following multivariable adjustment. CONCLUSIONS: A mean 7-day hemoglobin concentration of < 90g/L is associated with increased hospital mortality in patients with severe traumatic brain injury.     

Etomidate for intubation of patients who have sepsis or septic shock - where do we go from here?

Etomidate is an intravenous induction agent that is associated with hemodynamic stability during intubation. The agent is therefore attractive for use in critically ill patients who have a high risk of hemodynamic instability during this procedure. However, etomidate causes adrenal suppression, which itself has been associated with increased mortality in critically ill patients. The ongoing debate surrounding use of etomidate is thus centered on the immediate favorable hemodynamic profile versus the long-term risks of adrenal insufficiency, particularly in patients who have severe sepsis or septic shock.In this issue of Critical Care, Jung and colleagues reported on their single-center observational cohort study that compared etomidate with other induction agents to facilitate intubation in the 48 hours before the onset of shock in patients who had septic shock [1]. Based on local practice, all of these patients received hydrocortisone supplementation after a corticotropin stimulation test. This practice provided a unique opportunity to examine an important gap in the current literature: the risks and benefits of etomidate in septic shock in the context of universal hydrocortisone supplementation. Importantly, this study confirmed that immediate life-threatening complications, including severe hypotension, are common (37 of 102 patients) during the intubation period. Patients who received etomidate were more severely ill at baseline, which may explain why their physicians chose to use this agent. Consistent with other published results [2-4], patients who received etomidate had lower serum cortisol concentrations after intubation and a higher percentage of nonresponse to the corticotropin stimulation test compared with patients who received another induction agent (79% vs. 52%, P = 0.01). Patients who received etomidate also required a longer duration of hydrocortisone supplementation and a higher cumulative dose of norepinephrine compared with the non-etomidate group. Multivariable Cox regression demonstrated a decreased mortality rate in patients who had received etomidate (hazard ratio = 0.33, 95% confidence interval = 012 to 0.90, P = 0.03) after adjusting for severity of illness. It is important to note that the mortality signal favoring etomidate was contrary to the authors'' a priori hypothesis.The current study adds considerably to the limited evidence concerning use of etomidate in patients who have severe sepsis or septic shock. A post-hoc analysis of the Corticosteroid Therapy of Septic Shock (CORTICUS) trial showed that patients who received etomidate were more likely not to respond to corticotropin and had an increased mortality rate at 28 days (43% vs. 31%, P = 0.03) compared with patients who did not receive etomidate [2]. Use of hydrocortisone did not appear to substantively modify this relationship [5]. In CORTICUS, the median time between receiving etomidate and randomization to steroids (or not) was 14.5 hours (interquartile range = 4.25 to 28.4 hours) [5]. In contrast, the patients in the current study received hydrocortisone within 9 hours (interquartile range 5 to 19 hours) of intubation. Time may therefore be an important effect modifier in this analysis. Indeed, other authors have suggested that a brief course of corticosteroids should be given to patients who have received etomidate [6].Even if we take the results of this current study as evidence of equipoise in this issue, we have to ask ourselves ''What are the benefits of etomidate?'' Use of this drug is certainly associated with hemodynamic stability [7], which is why it is lauded as an agent for emergent rapid sequence induction [8]. However, there are several other means to achieve this goal. One possibility is to improve the process of care during intubation. Jaber and colleagues (same research group who authored the paper under discussion) have previously demonstrated a dramatic reduction in life-threatening cardiopulmonary complications from 34% to 21% (P = 0.03) after the introduction of a bundle of recommendations aimed at preventing intubation complications [9]. Of note, standardized induction agents, including etomidate, are an important component of this bundle, which also includes a fluid bolus, two operators, and the early use of vasopressors. Another possibility is to use alternate induction agents that have similar hemodynamic profiles to etomidate. In the KETASED trial, patients who required emergency intubation were randomized to etomidate or ketamine for induction [10]. There was no difference in terms of intubating conditions or immediate life-threatening complications between the two groups. Importantly there was also no difference in mortality between the two groups, although only 16% of the patients had sepsis. However, use of etomidate was associated with a much higher risk of adrenal insufficiency (86% vs. 48%, P <0.0001) when compared with ketamine.The central question regarding use of etomidate in patients who have severe sepsis and septic shock still remains ''Where do we go from here?'' This study by Jung and colleagues adds to the debate and asks further important questions. In particular, ''Does early steroid supplementation modify the risk of etomidate in these patients?'' However, in light of the conflicting data on clinical outcomes after use of etomidate and a readily available alternative agent that has a similar hemodynamic profile without the risk of adrenal suppression, namely ketamine, the use of etomidate in patients who have severe sepsis or septic shock continues to be controversial and potentially problematic.